Neoplasms

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Multiple Myeloma

Neoplasms, Plasma Cell

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Dose Escalating Cohorts of ACY-1215 in combination with pomalidomide and dexamethasone.

Escalating dose Cohorts to determine a potential Maximum Tolerated Dose to recommend for a dosing schedule.

ACY-1215 in combination with pomalidomide and dexamethasone

Sumit Madan, MD

To determine the maximum tolerated dose (MTD), if present, and dose schedule of ACY-1215 (ricolinostat) in combination with pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma.

To determine the maximum tolerated dose (MTD), if present, and to identify a recommended dose and schedule of ricolinostat administered in an alternative liquid formulation (ALF) (10mg/mL) in combination with pomalidomide and low-dose dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma.

To evaluate the safety and any anti-tumor activity of ricolinostat administered in combination with pomalidomide and dexamethasone as treatment for patients with relapsed or relapsed-and-refractory multiple myeloma, including duration of response.

To assess the Pharmacokinetics and Pharmacodynamics of all three medications administered in combination, and to assess the Pharmacokinetics of ricolinostat and pomalidomide specifically. An evaluation of the relationship between response and biomarkers relating to interacellular acetylation may also be completed.

Phase 1b Study Evaluating ACY-1215 (Ricolinostat) in Combination With Pomalidomide and Dexamethasone in Relapsed or Relapsed-and-Refractory Multiple Myeloma

A Phase 1b Multi-Center, Open Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Anti-Tumor Activity of an Alternative Liquid Formulation of ACY-1215 (Ricolinostat) In Combination With Pomalidomide and Low-Dose Dexamethasone In Patients With Relapsed and Refractory Multiple Myeloma

Identify the MTD of ACY-1215 administered in an alternative liquid formulation (ALF) if present, and identify a recommended dose and schedule. Patients will be followed for completion of 6 28-day Cycles of Study Treatment (for ITT Population analysis).

To assess the type, frequency, and severity of adverse events (AEs) and relationship of AEs to study drug.

Anti-tumor activity will be measured by objective response to treatment as assessed by the site Investigators using International Myeloma Working Group (IMWG) Uniform Response criteria. Anti-tumor activity will also be measured by duration of response, time to response, and time to progression. The Response rate will be the percentage of patients who achieve PR or better. The number of patients who have at least MR or better will also be collected as clinical benefit response. Progression-free survival (PFS) will be defined as the time from first dose of study treatment to the first documentation of disease progression or death from any cause during the study. For responders, time to tumor response and response duration will be analyzed.

Plasma levels of ACY-1215 will be measured to assess the single and multiple dose PK of AC-1215 in combination with pomalidomide and low-dose dexamethasone. Plasma levels of pomalidomide will be measured to assess the PK of pomalidomide in combination with ACY-1215 and low-dose dexamethasone.

Exposure response of ACY-1215 in combination with pomalidomide and low-dose dexamethasone, including biomarkers relating to intracellular protein acetylation, protein levels, mRNA and microRA expression profiles.

Celgene

Nervous System Diseases

Recurrence

Lymphoma

Leukemia

Central Nervous System Neoplasms

Nervous System Neoplasms

Lymphosarcoma

Amino Acids

Neratinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

There are 2 parts to this study: a Phase I part and a Phase II part. The Phase I portion is known as the dose escalation phase where neratinib will be tested in groups of 3-6 patients to establish the maximum tolerated dose (MTD). The phase II portion will determine whether the MTD shows a response to the tumor.

Neratinib will be administered orally, or through existing gastrostomy feeding tube, once a day with food, preferably in the morning, continuously for 28-day cycles, with no rest between cycles. Dose will be scaled by body surface area (BSA).

Tanya Trippett, MD

The purpose of this study is to test the safety of neratinib at different dose levels and to find out what effects, good and bad, it has on the patients and the cancer.

Safety and Dose Finding Study of Neratinib in Children and Young Adults With Cancer That Has Returned or Not Responded to Treatment

A Phase I/II Study of Neratinib in Pediatric Patients With Relapsed or Refractory Solid Tumors

NCI CTCAE Version 4.0.Definition of Hematologic Dose-Limiting Toxicity (solid tumor cohort only) Any hematologic toxicity as indicated: Febrile neutropenia defined as Grade 3 or 4 neutropenia with fever ≥ 38.5°C and /or infection requiring antibiotic or antifungal treatment Grade 4 neutropenia lasting \> 7 days Grade 4 thrombocytopenia lasting \> 7days Any drug-related adverse experience, regardless of grade, leading to a dose reduction of a study drug. Non-Hematologic Dose-Limiting Toxicities: Non-hematologic dose-limiting toxicity will be defined as any Grade 3, 4 or 5 nonhematologic toxicity with the specific exception of: Any grade diarrhea that occurs in the setting of poor compliance with supportive measures that last for \< 48 hours Any grade dehydration related to diarrhea that occurs in the setting of inadequate compliance to supportive care measures that last for \< 48 hours.

Milton S. Hershey Medical Center

M.D. Anderson Cancer Center

Stanford University

Arkansas Children's Hospital Research Institute

Alberta Children's Hospital

Phoenix Children's Hospital

University of Texas

Memorial Sloan Kettering Cancer Center

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Dermatologic Agents

Analgesics

Tretinoin

Cytarabine

Mitoxantrone

Gemtuzumab

Antimetabolites

Antiviral Agents

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Gemtuzumab Ozogamicin

45 mg/m2 p.o. day 4-6 15 mg/m2 p.o. day 7-28

All-trans-Retinoid Acid

Richard F Schlenk, Dr. med.

GO-A-HAM:

Gemtuzumab Ozogamicin 3g/m² day 1 Cytarabine 3g/m² bid days 1-3 Mitoxantrone 12mg/m² days 2,3 All-trans Retinoic acid 45mg/m² days 4-6 and 15 mg/m² days 7-28

Primary refractory AML is associated with an extremely poor prognosis \[1,2\]. In the AMLHD93 trial conducted by the AMLSG ULM, patients refractory to the first induction therapy with ICE (idarubicin, cytarabine, etoposide) had an overall survival of 12% after 5 years \[1\]. All patients alive in this cohort had received allogeneic transplantation. Therefore, we assigned allogeneic transplantation in our consecutive trial, AMLHD98A, to all primary refractory patients \[3\]. However, the main problem in this patient group remains achieving a partial (PR) or complete (CR) remission to a salvage therapy. Additionally, the pre-transplant disease status is an important prognostic factor in most studies of allogeneic transplantation, regardless dose intensified or dose reduced conditioning regimens are used \[4,5,6\]. Since 1993, in all studies of the German-Austrian-AMLSG response-adapted treatment strategies had been used. Within the AMLHD93 trial, refractory patients were assigned to an intensified second induction regimen with S-HAM (age\<55 years) \[7\] or HAM (age 55 to 60 years) \[1\], and in the AMLHD98A trial, with A-HAM \[3\]. The incorporation of all-trans-retinoic acid was based on in vitro data \[8-13\] and by our randomised AMLHD98B study for elderly AML-patients showing a benefit in primary response and survival for patients assigned to standard induction therapy in combination with ATRA \[14\].

To compare the different salvage therapy strategies, we performed an as-treated analysis in primary refractory patients of the different cohorts. Although refractory to the first induction therapy with ICE, nine patients received a second cycle ICE. The results summarized in table 1 showed an improved response rate (CR and PR) for patients treated with the A-HAM protocol and thus leading to a higher proportion of patients receiving an allogeneic transplantation. Survival analysis showed so far no difference between the 4 different groups. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 conjugated to Calicheamicin. The efficacy and the toxicity profile has been evaluated in several studies, so far the substance is approved for the monotherapy in relapsed AML-patients in a dose of 9mg/m² q 14d \[15\]. However, used as a single agent the efficacy is limited and not durable. Therefore, several trials have evaluated GO in combination with conventional chemotherapy \[16,17\]. In the MRC study a dose of 6 mg/m² given once at day 1 was associated with an increased liver toxicity and therefore the study continues with a dose of 3 mg/m² once at day 1 of induction therapy \[17\]. In summary, the available data for combination therapy showed efficacy of GO in phase II trials. The dose limiting toxicity was defined in the MRC trial at 6 mg/m². Therefore we consider GO in combination with A-HAM for primary refractory adult AML patients. Because all primary refractory patients are candidates for an allogeneic transplantation special considerations have to be taken with respect to the development of VOD after allogeneic transplantation. One recent report suggests a substantial risk for VOD for patients receiving an allogeneic transplantation after a therapy with GO \[18\]. In this report the odds ratio for VOD after a therapy with GO within 3.5 months before allogeneic transplantation was 21.6 (95%-confidence interval 4.2-112.2%). However, this report is based on 62 patients and the dosage of GO used was 6mg/m² and 9mg/m². Therefore, holding in mind the risk of VOD after GO exposure and the extremely poor prognosis of primary refractory patients the treatment approach combining A-HAM with GO with a dose of 3mg/m² is justified.

Gemtuzumab Ozogamicin in Combination With A-HAM in Refractory AML (GO-A-HAM)

Phase II Study on Gemtuzumab Ozogamicin in Combination With All-trans-Retinoic Acid, High-dose Cytarabine and Mitoxantrone in Patients With Primary Refractory Acute Myeloid Leukemia

University of Ulm

Prof. Dr. Reinhard Marre

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1b Study Evaluating ACY-1215 (Ricolinostat) in Combination With Pomalidomide and Dexamethasone in Relapsed or Relapsed-and-Refractory Multiple Myeloma	NCT02189343	Multiple Myelom...	ACY-1215 in com...	18 Years -	Celgene
Safety and Dose Finding Study of Neratinib in Children and Young Adults With Cancer That Has Returned or Not Responded to Treatment	NCT02932280	Solid Tumor Central Nervous... Lymphoma Leukemia	Neratinib	3 Years - 21 Years	Memorial Sloan Kettering Cancer Center
Phase 1b Study Evaluating ACY-1215 (Ricolinostat) in Combination With Pomalidomide and Dexamethasone in Relapsed or Relapsed-and-Refractory Multiple Myeloma	NCT02189343	Multiple Myelom...	ACY-1215 in com...	18 Years -	Celgene
Safety and Dose Finding Study of Neratinib in Children and Young Adults With Cancer That Has Returned or Not Responded to Treatment	NCT02932280	Solid Tumor Central Nervous... Lymphoma Leukemia	Neratinib	3 Years - 21 Years	Memorial Sloan Kettering Cancer Center
Gemtuzumab Ozogamicin in Combination With A-HAM in Refractory AML (GO-A-HAM)	NCT00143975	Leukemia, Myelo...	Cytarabine Mitoxantrone Gemtuzumab Ozog... All-trans-Retin...	18 Years - 60 Years	University of Ulm

Spots Global Cancer Trial Database for refractory disease